Overview: Anti-NMDA receptor antibodies in brain dysfunction: lessons from lupus Program Project Director: Dr. Betty Diamond This is a proposal to study the contribution of a particular autoantibody to aspects of neuropsychiatric lupus. Four proposed research projects derive from the observation that a subset of anti-DNA antibodies present in the serum of lupus patients cross-reacts with NMDA receptors (NMDARs) and is capable of mediating apoptotic death of neurons leading to hippocampal (cognitive) or amygdala! (behavioral) impairment. The immediate goals of the Program are four-fold;each goal is addressed in a specific project: Project 1: to determine whether there is variability in the electrophysiologic signature of monoclonal antibodies to the NMDAR corresponding with functional variability;Project 2: to determine whether maternal antibodies to the NMDAR cause impairment in fetal brain development;Project 3: to determine if antibody-mediated impairment of the hippocampus or amygdala can be detected by functional magnetic resonance imaging in patients with lupus and Project 4: to determine whether we can develop therapeutic strategies for neuroprotection. The Program includes an Administrative Core with an Advisory Committee to facilitate the research agenda. There is a Behavior Core, a Histology Core and a Monoclonal Antibody Core to provide high quality, uniform quality immunohistology and behavioral analysis as well as standardized batches of monoclonal anti-NMDAR antibodies for Projects 1, 2 and 4. This Program represents a multidisciplinary approach to a perplexing and disabling problem in patients with systemic lupus. The investigators have track records of productivity and collaborative interactions that ensure the success of this endeavor.